This proposal will develop foamy virus (FV) vectors for the treatment of leukocyte adhesion deficiency (LAD). In LAD, mutations in the CD18 gene prevent the migration of white blood cells (leukocytes) into tissues, resulting in life-threatening bacterial infections. Transplantation of autologous hematopoietic stem cells (HSCs) transduced by CD18-expressing vectors could cure this disease. However, human and large animal HSCs are difficult to transduce efficiently, and integrating vectors based on murine leukemia virus (MLV) have been shown to cause leukemia by activating nearby cellular proto-oncogenes. FVs are retroviruses and vectors based on them are able to efficiently deliver genes to HSCs. They are not pathogenic so FV vectors may be safer than other types of retroviral vectors. Here FV vectors will be used to deliver the canine CD18 gene to the HSCs of dogs with canine LAD (CLAD). These HSCs will then be transplanted into CLAD dogs, where they will differentiate into mature blood cells that express CD18. If adequate CD18 levels are obtained, the transplanted dogs should improve clinically and avoid an early death due to infections. The data will be used to determine the efficiency of transferring genes into canine HSCs with FV vectors. Integration site analysis will establish how many different transduced cell clones contributed to blood formation, and whether there was selective expansion of particular clones. The transplanted animals will be followed long-term to look for potential side effects, including the development of leukemia. Different conditioning regimens used to promote engraftment of transplanted cells will be tested. FV vectors that use different promoters will be evaluated. FV vectors will be compared to similar lentiviral vectors that express CD18 to determine the best type of vector for HSC gene therapy of LAD. These experiments will determine if FV vectors can efficiently transfer genes to canine bone marrow stem cells, and if FV vectors expressing CD 18 can cure CLAD. This could lead to the development of new treatments for LAD, as well as other genetic or acquired blood diseases, which could improve the health of many Americans. If shown to be safe and effective, the FV vectors tested in the proposed experiments could then be used in human clinical trials to treat LAD.